Project Summary Glioblastoma (GBM) is the most common primary malignant brain tumor in veterans. The prognosis for GBM is dismal and there is an urgent need for novel treatments. The receptor interacting protein (RIP1, RIPK1) has emerged as a central regulator of cell death in cell stress, inflammation, and development. Depending on the cellular context, RIP1 is known to either activate the transcription factor NF-?B and promote cell survival, or induce apoptotic or necrotic cell death in response to a number of stressful stimuli. Recent studies have shown that activation of NF-?B plays an important role in the pathogenesis of GBM. In this proposal, we propose to examine the role of RIP1 as a cell life death/switch in glioblastoma (GBM). A characteristic histopathological feature of GBMs is the presence of necrosis within the tumors. We have previously shown that RIP1 is expressed in GBM and confers a worse prognosis. In this proposal we examine the hypothesis that the RIP1 switch in GBM is regulated by EGFR signaling. The experimental goals of this project are to examine whether RIP1 is essential for tumor formation in an experimental model of GBM, and to investigate whether RIP1 regulates the induction of necrotic cell death in GBM. We aim to elucidate the mechanisms used by a mutant EGFRvIII to activate the oncogenic potential of RIP1 and the mechanism used the EGFR wild type (EGFRwt) to switch RIP1 to a cell death mode using an experimental intracranial mouse model of GBM. Additionally, we investigate RIP1 as a target for treatment in GBM using two alternative hypothesis. Hypothesis A: RIP1 silencing will result in inhibition of tumor growth in GBM. Hypothesis B: Activation of the cell death function of RIP1 using the EGFR network will eliminate GBM cells in vivo. Thus, RIP1 studies in GBM have the potential to significantly impact understanding of GBM and improve its treatment.